Conventional polyvinyl alcohol (PVA) is a widely used polymer in fibers, adhesives, films, membranes, fishing baits, and drug delivery vehicles. PVA is also commonly used as a base for various pharmaceutical and non-pharmaceutical chewing gums. Co-polymers of PVA with acrylic or methacrylic acid have been studied for controlled drug delivery and for pH-sensitive smart drug delivery vehicles (Ranjha et al, “pH-sensitive non-crosslinked poly(vinyl alcohol-co-acrylic acid) hydrogels for site specific drug delivery,” Saudi Pharmaceutical Journal, 7(3):137-143 (1999); Hirai et al, “pH-Induced structure change of poly(vinyl alcohol) hydrogel crosslinked with poly(acrylic acid),” Angewandte Makromolekulare Chemie, 240:213-219 (1996); Barbani et al, “Hydrogels based on poly(vinyl alcohol-co-acrylic acid) as innovative system for controlled drug delivery,” Journal of Applied Biomaterials and Biomechanics, 2:192 (2004); and Coluccio et al, “Preparation and characterization of poly(vinyl alcohol-co-acrylic acid) microparticles as a smart drug delivery system,” Journal of Applied Biomaterials and Biomechanics, 2:202 (2004)).
Conventional PVA hydrogels have also been extensively studied for biomedical applications, for example, in soft tissue applications wherein their high water content and rheology are well suited. Crosslinking has been studied as a mechanism for controlling the mechanical properties of PVA, including cross-linking by addition of chemical agents, e.g. glutaraldehyde (Canal et al, “Correlation between Mesh Size and Equilibrium Degree of Swelling of Polymeric Networks,” Journal of Biomedical Materials Research, 23:1183-1193 (1989); Kurihara et al, “Crosslinking of poly(vinyl alcohol)-graft-N-isopropylacrylamide copolymer membranes with glutaraldehyde and permeation of solutes through the membranes,” Polymer, 37:1123-1128 (1996); and Mckenna, et al, “Effect of Cross-Links on the Thermodynamics of Poly(Vinyl Alcohol) Hydrogels,” Polymer, 35:5737-5742 (1994)), crosslinking by irradiation/photopolymerisation, and crosslinking by cryotropic gelation (Stauffer et al, “Poly(Vinyl Alcohol) Hydrogels Prepared by Freezing-Thawing Cyclic Processing,” Polymer, 33:3932-3936 (1992); Urushizaki et al, “Swelling and Mechanical-Properties of Poly(Vinyl Alcohol) Hydrogels,” International Journal of Pharmaceutics, 58:135-142 (1990); and Peppas et al, “Controlled Release from Poly(Vinyl Alcohol) Gels Prepared by Freezing-Thawing Processes,” Journal of Controlled Release, 18:95-100 (1992)).
However, glutaraldehyde is known to be toxic to cells; accordingly, hydrogels prepared with such chemical crosslinking agents have limited applications unless the absence of unreacted toxic entities is reassured. Irradiation-crosslinked PVA hydrogels have been described for controlled release of biologically active substances (Penther et al, Jena Math. Nat. Wiss. Reihe, 36:669 (1987)). However, these gels are generally weak (Yoshii et al, Radiation Physics and Chemistry, 46:169-174 (1995)), and the irradiation methods are typically expensive and difficult for industrial scale-up.
Cryotropic gelation, i.e., gel formation upon consecutive freezing, for example in a temperature range between −5 and −196° C., and thawing, is a physical method of gel formation which is suited best for pharmaceutical and biotechnological applications as it avoids use of potentially hazardous cross-linking agents or irradiation to manufacture firm hydrogels. Such cryogels can act as drug delivery vehicles useful in, e.g., controlled release formulations. Early cryogels were made in the 1940s in Germany where sponges were produced by freezing of starch paste. Cryogels from PVA solutions were described in the 1970s for manufacturing jelly fish baits (Inoue et al, “Water-resistant poly(vinyl alcohol) plastics,” Japanese Patent No. 47-012854 (1972)). Descriptions of cryogelling properties of polyvinyl alcohol polymers are provided by Nambu, “Rubber-like poly(vinyl alcohol) gel,” Kobunshi Ronbunshu, 47:695-703 (1990); Peppas et al, “Reinforced Uncrosslinked Poly (Vinyl Alcohol) Gels Produced by Cyclic Freezing-Thawing Processes—a Short Review,” Journal of Controlled Release, 16:305-310 (1991); and Lozinsky, “Cryotropic gelation of poly(vinyl alcohol) solutions,” Uspekhi Khimii, 67:641-655 (1998). PVA-based hydrogel systems have been used to develop various stimuli-responsive pharmaceutical systems which undergo significant volume transitions with relatively small changes in the environmental conditions, e.g. pH, magnetic field, or light (Hernandez et al, “Viscoelastic properties of poly(vinyl alcohol) hydrogels and ferrogels obtained through freezing-thawing cycles,” Polymer, 45(16):5543-5549 (2004)).
PVA is probably the most common polymer among cryogelling agents for biomedical applications because it is non-toxic and biocompatible. Further, the structure-functionality relationship of PVA-based cryogels has been extensively described. Generally, PVA gels with larger molecular mass form firmer cryogels than analogues with lower molecular mass (Lozinsky, supra). This is because polymer chain elongation increases the possibility of entanglement between adjacent chains and eventually local crystallization. However, high molecular mass polymers are known to have lower solubility. Similarly, higher density of available side chains produces firmer gels than analogues with lower degrees of branching (Id.).
The mechanism of cryogel formation is complex. In brief, it is believed that during freezing, local areas of high polymer concentration are formed and promote crystallite formation and cross-linking between polymer chains resulting in a macroporous mesh (Domotenko et al, “Influence of Regimes of Freezing of Aqueous Solutions of Polyvinyl-Alcohol and Conditions of Defreezing of Samples on Properties of Obtained Cryogels,” Vysokomolekulyarnye Soedineniya Seriya, A 30:1661-1666 (1988)). As a result, PVA chains form the ordered structures known as microcrystallinity zones (Yakoyama et al, “Morphology and structure of highly elastic poly(vinyl alcohol) hydrogel prepared by repeated freezing-and-melting,” Coll. Polym. Sci., 264:595-601 (1986)). They act as junction knots which in turn arise only when the OH groups are free to participate in interchain interactions. Inasmuch as an industrial PVA is commonly manufactured by the saponification of poly(vinyl acetate), the degree of deacetylation along with the polymer molecular weight and tacticity are crucial in determining the ability of PVA solutions to gel and particularly to gel via cryotropic gelation, since the residual acetyl groups will interfere with the coupling of the sufficiently long intermolecular contacts needed for the formation of PVA crystallites. Therefore, for the preparation of rigid cryogels of PVA, it is necessary to use highly-deacetylated PVA (Watase et al, “Rheological and DSC Changes in Polyvinyl-Alcohol) Gels Induced by Immersion in Water,” Journal of Polymer Science Part B-Polymer Physics, 23:1803-1811 (1985)).
While hydrogels in general can have a range of mechanical properties depending on their chemistry and water content, they generally have a relatively low mechanical strength (Hydrogels in Medicine and Pharmacy: Vol. I-III, Peppas, Ed., CRC Press Boca Raton, Fla. (1986). Currently known PVA-based cryogels typically form firm gel structures at concentrations around 14-16% by wt (Lozinsky, supra) and additional cross-linking agents may often be used. Concentrated PVA solutions are typically used for the preparation of mechanically rigid cryogel matrices; however, very concentrated (>20% by wt) solutions of PVA are excessively viscous, especially when the polymer molecular weight exceeds 60-70 kDa. (Lozinsky et al, “Poly(vinyl alcohol) cryogels employed as matrices for cell immobilization. 3. Overview of recent research and developments,” Enzyme and Microbial Technology, 23:227-242 (1998)). The Lozinsky Russian Patent No. 2003-131705/04 discloses that PVA-based cryogels are formed at concentrations between 3-25% by wt with the addition of a surface active agent and that the addition of surface active agents (herein and elsewhere also referred to as emulsifiers) was found crucial for obtaining both physical crosslinking between adjacent polymer chains and high macro-porosity. The Lozinsky patent further discloses that the chemical character of the emulsifier (cationic, anionic, or amphoteric) is not critical as long as it was present in the composition.
As noted, PVA is typically manufactured by the saponification of poly(vinyl acetate). A commonly used polymerization route of polyvinyl-acetate-based polymers utilizes emulsifiers or protective hydrocolloids for successful polymerization. Further, organic solvents are conventionally used in the process (i.e. the so-called varnish method), which are hazardous and environmentally unfriendly and therefore require special handling. In addition, during saponification of vinyl acetate products, a hard jelly-like mass is conventionally formed and is then broken using high-shear homogenizers, requiring a significant input of energy. GB Patent No. 835,651 discloses a vinyl acetate polymer prepared with a limited amount of acrylamide to form a stable dispersion that yields a hard water-resistant film on drying at a high temperature.
In view of the non-toxic and biocompatible nature of PVA, further improvements in PVA hydrogels are desirable to allow expanded use of PVA in various applications.